Hello Dear colleges;
I) As we know that cancer cells grow up in a hypoxic conditions; "less oxygen, more growth". Morever; Angiogenesis maintain blood flow to the growing tumor tissues, providing nutrients and O2 for helping cancer cells to build up (even that we know that cancer cells don't like O2).
In other words, more cells more demand causing more hypoxia!!!!??? (how this work!!!).
First questions:
1) How these cells becomes hypoxic even thought of the presence of new vessels blood that supply oxygen??
2) is that means that tumours neglect and uncared for O2??!!!
II) During aerobic Glycolysis, tumours produce Lactate and H+ which leads to microenvironment acidosis (Warburg Effect).
3) Why cancer cells like to use fermentation process with which we've just got 2ATP per Glucose molecule rather than oxidative phosphorylation (36-38ATP per 1mole Glucose); EVEN the frenquency of oxygen supply!!! For Note, some studies mention that in some type of cancers the mitochondria is functionnal)!!
In addition, some studies say that: for a simple adaptation to intermittent hypoxia in pre-malignant lesions, they altered the glucose metabolism!!
Thank you for your consideration and help :)
Sincerely,
Fouzia
In the first place new vessels formed through angiogenesis brought up by the tumor, are functionally ineffective for keeping up with the need of nutrients and O2.
So that major areas of the tumor are in hypoxic and acidic areas. These areas contain glycolytic cells. There are areas with better supply of O2 and cells in this other areas remain in OX-PHOS metabolism. There are in these oxigenated areas cells that take up lactic acid from ECM and metabolize it via OX-PHOS.
Tumors are metabolically heterogeneous coexisting three different cells: glycolytic, oxidative and lactic oxidative.
This said, the energy ecuation of glycolysis vs oxidative metabolism is 2 vs 38 ATP. But malignant cells consume around 10 to 20 times more glucose which compensates for any insufficient production of ATP.
OX-PHOS creates ROS while fermentation does not. Tumor cells are in continuos fight against an increased ROS production. Glycolysis is one if the responses to decrease ROS.
Finally glycolytic metabolism allows a major deviation of netabolites in order to create building blocks for structures like membranes and nuckeic acids. It permits an important deviation toward PPP (pentoses pathway) necessary for building nucleic acids.
The problem is very complex and not fully understood, but slowly we are finding out the advantages of glycolytic metabolusm for tumors.
The following paper will answer your questions with more detail:
Article Energy metabolism of cancer: Glycolysis versus oxidative pho...
We cannot not to mention the role of HIF as a factor for adaptation to the hypoxic microenvironment. HIF has a very large amount of phisiopathologic effects, both on the microenvironment and the tumor itself , including neoangiogenesis, and epithelial mesenchimal transition, (which ultimately lead to metastatic diffusion). The Warburg effect and the impairment of TCA cycle, with increase of succinate, have a pivotal role in HIF stabilization.
It is avery goog complex question. I agree with Dr. Tomas Koltai, He covered many issues nicely. The heterogeneous nature of the tumor makes everything possible. The two opposite situations may co-exist together depending on the tumor microenvironment.
Thank you for your respond dear friends, I really appreciate it. I will take a look on all the papers you've attached. Thanks again
Fouzia
I agree with Dr. Tomas Koltai, who covered the issue in a very comprehensive manner !
I want just to stress a point, that has already been mentioned by other colleagues above, which has to do with the mechanism of hypoxia-driven angiogenesis, In short, in hypoxic tumor cells the VHL protein undergoes prolyl-hydroxylation, subsequently binding to HIF which instead of being driven to proteasome for degradation, it gets stabilized and dimerizes, then translocating to the nucleus where it binds to DNA regions called angiogenesis-related elements (AREs) and drives genes for VEGF, glucose transport (Glut-1), eryhropoietin , etc...!!!
In general, it can be said that in a given tumor cell population there is a large degree of heterogeneity; that said implies that certain areas are highly vascular with adequate blood supply and cell survival are based onaerobic glycolysis takes, whereas other areas have poor blood supply and rely largely on anaerobic glycolysis and cells grow under hypoxic conditions and produce lactic acid. The fact is that it is the hypoxic cells that promote angiogenesis, whic in turn drives tumor growth and metastases...!!!
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